Androgens in Health and Disease.pdf - E Library

16 Winters and Clark
Table 2
Tissue Distribution of Steroid 5-Reductase Isozymes in Man
Tissue Type 1 Type 2
Prostate, epididymis, seminal vesicle, genital skin – ++
Liver + +
Nongenital skin ++ –
Testis, ovary, adrenal, brain, kidney – –
Source: ref. 129.
Studies using radiolabeled androstenedione indicate that the testes of normal men
produce only about 15% of the circulating estrogens (134). Instead, most estrogen in men
is from aromatase in adipose and skin stromal cells, with a lesser contribution from aortic
smooth muscle cells, kidney, skeletal cells, and the brain. The promoter sequences of the
P450 aromatase genes are tissue-specific because of differential splicing, but the translated
protein appears to be the same in all tissues. Thus, glucocorticoids and serum
growth factors (e.g., IL-6 and leukemia inhibitory factor) stimulate androgen bioconversion
to estrogen in human adipose stromal cells but not in testis. Aromatase in adipose
tissue leads to increased bioconversion of androgens to estrogens with obesity (135) and,
perhaps, with aging.
Awareness of the importance of estradiol in men has increased substantially with the
description of an adult man with an inactivating mutation of ER- and of men with
mutations of the CYP19 aromatase gene (136). Striking findings in these men include
high levels of LH and testosterone, delayed epiphyseal closure and osteopenia, as well
as hyperinsulinemia in the ER--deficient man. Estrogen synthesis in target tissues may
play an important role in the function of these tissues. For example, testosterone converted
to estradiol in the brain is thought to mediate masculinization behavior, at least
in rats (137), and it is important in the testicular feedback inhibition of GnRH. Both
ER- and ER- are expressed in the testis. ER- is found in testicular Leydig cells and
ER- is present in seminiferous tubules. Studies of the ER- knockout mouse indicate
that estrogens regulate the efferent ductules of the testis, whereas male mice deficient in
aromatase, although fertile in young adulthood, progressively develop infertility (138).
Therefore, conversion of testosterone to estrogens is essential for male fertility.
The reversible interconversion between testosterone and the inactive 17-ketosteroid,
androstenedione, is catalyzed by the 17HSDs. These enzymes also catalyze the
interconversion between the biologically active estrogen, estradiol, and the relatively
inactive estrogen, estrone. Several distinct 17HSD isoenzymes have been characterized
with unique tissue distribution patterns that imply a specific function, and at least
seven 17HSDs have already been identified in humans. 17HSD-I is a reductase found
in Leydig cells, where it is essential for testosterone biosynthesis, as described earlier.
17HSD-II is a dehydrogenase that is widely expressed in tissues, including the prostate,
liver, and kidney and in the breast and uterus in females. 17HSD types I, III, IV, and
V are found in the brain (139).
The major route of metabolism of testosterone is by a family of hepatic microsomal
CYP P450 enzymes (P450 3A isoforms) that produce monohydroxylated products at
the 2, 6, 7, and 16 positions. Oxidation of the D ring produces the 17-ketosteroids
androsterone (3-hydroxy-5-androstane-17-one) and etiocholanolone (3-hydroxy-